Use of undercylenic acid to treat herpes labialis

ABSTRACT

Warm-blooded animals are treated for Herpes simplex virus-I by administering to the animal a dosage, effective to alleviate the symptoms of the virus, of undecylenic acid and at least one pharmaceutically acceptable carrier, wherein the compound is in the range of from about 1 to about 95% by weight of the composition.

This is an application for reissue of U.S. Pat. No. 4,520,132 grantedMay 28, 1985..Iaddend.

BACKGROUND OF THE INVENTION

This invention relates to a method of treating Herpes Simplex Virus-I(called herpes I) infections of the labial area in mammals and moreparticularly to a method of treating herpes I infections of the labialarea in mammals with an antiviral composition containing undecylenicacid, and at least one pharmaceutically accepted carrier.

Herpes Labialis is an acute and recurring painful vesicular eruption ofthe oral mucosa in the vermilion borders of the lips. The causativeagent is herpes virus, type I, and the initial infection usually occursin childhood. Mild trauma such as sunburn, chapping, or fever may be apredisposing factor for a recurrent eruption; the common name for thelesion is a "cold sore".

The onset of a recurrent lesion is usually a feeling of fullness with aburning or itching sensation on the lips. This occurs before the typicalvesicle develops. Vesicular lesions usually exist for several hoursbefore the vesicle breaks or the fluid becomes secondarily infected. Thelesions then become yellowish and crusted. The condition is selflimiting, symptoms generally subsiding after from about 7 to about 10days.

No prior art is known which discloses the use of undecylenic acid forthe treatment of herpes I.

SUMMARY OF THE INVENTION

This invention is directed to a method of treating herpes I infectionsof the labial area in mammals comprising administering to the mammal inneed of said treatment an effective amount for treating the herpes Ivirus of a composition of undecylenic acid and at least onepharmaceutically acceptable carrier, wherein the compound is from about1% to about 95% (preferably 2 to about 25%) by weight of thecomposition.

DETAILED DESCRIPTION OF THE INVENTION

The undecylenic acid drug of this invention can be administered in theantiviral treatment according to this invention by any means thateffects contact of the active ingredient compound with the site of virusinfection in the body, after the infection becomes visible. The normaldosage form of the drug is topical application. The dosage form may be asolution, gel, emulsion, suspension, paste, ointment, powder, granule,aerosol product, or other suitable formulation. The dosage of the drugadministered will be dependent upon the virus being treated, i.e. herpesI, the frequency of treatment, and the effect desired. Generally in man,a daily topical dosage of active ingredient will be from about 5milligrams to about 50 milligrams per application, although lower andhigher amounts can be used. Thge dosage is generally administered byrepeated topical applications and the frequency of application woulddepend on the formulation and concentration of undecylenic acid. From 2to 6 applications per day are usual, but three times per day arepreferable.

The active ingredient, the drug, can be employed in useful compositionsaccording to the present invention in such dosage forms as solution,semisolid, solid, and solid form. These dosage forms preferably deliverfrom about 5 milligrams to about 50 milligrams of active ingredient perapplication, with a range from about 10 milligrams to about 25milligrams per application being preferred. In these dosage forms theantiviral composition will contain at least one non-toxicpharmaceutically acceptable carrier for the active ingredient.

Examples of the non-toxic carriers or adjuvants are viscosity enhancerssuch as bentonite, cellulose (e.g. methylcellulose, ethylcellulose, andcarboxy methylcellulose) tragacanth, glyceryl monostearate, cetylalcohol, stearyl alcohol, synthetic spermaceti, and stearic acid; pHmodifiers such as dibasic sodium phosphate, citric acid, and sodiumhydroxide; preservatives such as methylparaben, propylparaben, benzoicacid, and benzyl alcohol; stability enhancers such as sodium bisulfiteand ascorbic acid; coloring such as food, drug and cosmetic (FD&C) anddrug and cosmetic (D&C) colors certified by the Food and DrugAdministration (FDA); solvents such as water, alcohol (e.g. ethylalcohol, propyl alcohol and isopropyl alcohol), polyethylene glycol, andpropylene glycol; suspending agents such as kaolin, celluloses (e.g.methylcellulose, ethylcellulose, and carboxy methylcellulose), acaciaand tragacanth; emulsifying agents such as glyceryl stearate,decyloleate, cetearyl alcohol, polysorbate 80 and triethanolamine; andhumectants such as myristyl myristate.

For effective treatment of Herpes Simplex Virus-I the pharmaceuticallyacceptable carriers are chosen to allow penetration of an effectiveconcentration of the undecylenic acid at the site of infection. Methodsof preparing ointments, creams, lotions and other topical preparationsto permit various degrees of tissue penetration are well known inpharmaceutical chemistry and several variations of undecylenic acidformulations are envisaged by this invention. The following typicalembodiments of pharmaceutical compositions of this invention are givenbut are not limiting in any way: (all percentages are by weight ofcomposition)

    ______________________________________                                        Undecylenic Acid Solutions                                                    Undecylenic acid       10%                                                    Propyl alchol          40%                                                    Propylene glycol       20%                                                    Triethanolamine        2%                                                     Polysorbate 80         1%                                                     Water                  27%                                                    Undecylenic Acid Lip Balm                                                     Undecylenic acid       10%                                                    Castor oil             10%                                                    Beeswax (synthetic or  40%                                                    natural)                                                                      Butyl stearate         20%                                                    Arachidyl propionate   16.9%                                                  Butylated hydroxy-     0.1%                                                   toluene                                                                       Flavor/fragrance       3%                                                     Undecylenic Acid Cream                                                        Undecylenic acid       10%                                                    Sorbitol 70%           15%                                                    polyethylene glycol 300 monostearate                                                                 7%                                                     Stearic acid           5%                                                     Lanolin, anhydrous     4%                                                     White Petrolatum       3%                                                     Treithanolamine        3%                                                     Methyl paraben         0.5%                                                   Polyoxyethylene        0.25%                                                  laurate                                                                       Perfumes               0.25%                                                  Water                  50%                                                    ______________________________________                                    

EXAMPLE I

The undecylenic acid was tested for its antiviral activity againstherpes I using a method that was developed by Sidewall.

The hair was shaved from both sides of female guinea pigs. These femaleguinea pigs were then innoculated with the herpes I virus for producingthe lesions by spreading the virus over a measured area approximately 10millimeter square (mm²) and scratching within the area 10 timeshorizontally and 10 times vertically using an innoculating needle. Theguinea pigs were then divided up into groups of five per group. Thetreating composition (undecylenic acid dissolved in a vehicle of 40%propyl alcohol, 20% propylene glycol and 27% water at a concentration of1 gram of UDA per ten milliliters of vehicle) was applied topically atthe same dosage three times a day for seven days. Each animal wastreated daily beginning fifteen hours after innoculation by spraying theskin lesion and surrounding skins with three sprays per lesion pertreatment whereby each spray delivered 0.15 grams of solution containing15 milligrams of undecylenic acid, a dosage of approximately 45milligrams per treatment. A placebo of the vehicle was similarly appliedto a second group of guinea pigs. The animals were observed each day forthe ten day period and the lesions, when visible, were measured andscored on the third, sixth, and tenth day. No lesions appeared until thesecond day after the drug treatment had begun (i.e., 21/2 days afterinnoculation) and lesion measurements were first made on the third dayof drug treatment (31/2 days after innoculation).

The animals were observed and scored by the same person who equated theseverity of the lesion in the animal with an arbitrary number,independent of the size of the lesion. A scale of 0 to 4 was used toscore the animals where 0 meant that no lesion was formed (i.e.,normal); 1 meant that a faint scab had developed; 2 meant that amoderate scab with a slight blister had developed; 3 meant that a heavyscab with blisters had developed; and 4 meant that a very heavy scabwith blisters and new vesicles had developed. The lesions were measuredand compared to untreated control values.

Calculations for antiviral activity of the drug were based on theaverage of the daily average scores for the third, sixth, and tenth daysfor each group of animals. On the third, sixth, and tenth days thevalues for the lesion size and lesion severity were measured and themean average for the groups was recorded in Table I.

The known antiviral compound ribavirin (a 5% solution), was evaluated asa control following the same technique described above.

                  TABLE I                                                         ______________________________________                                        Observations of Lesion on Days Indicated                                      PLACEBO                      5% RIBAVIRIN                                     Size              10% UDA        Size                                         *Days (mm)    Rating  Size (mm)                                                                              Rating                                                                              (mm)  Rating                             ______________________________________                                        3     14.8    2.8     11.2     1.8   9.1   1.0                                6     13.8    1.7     10.0     1.1   9.0   1.0                                10    7.5     0.9     0        0     4.6   0.7                                ______________________________________                                         *after initial innoculation                                              

This data in Table I shows that on the tenth day when using a tenpercent (10%) undecylenic acid the lesions had completely healed whilethe five percent (5%) ribavirin solution treated lesion still exhibiteda faint scab; thereafter, the control lesions started to get largeragain whereas te lesions treated pursuant to the present inventionremained dormant with the ribavirin (control) treatment three lesionsrecurred after the tenth day.

When an attempt was made to treat animals for herpes I with an ointmentwhich contained 5% undecylenic acid and 20% zinc undecylenate, thisointment had no significant effect on the herpes I virus. The techniqueused to evaluate the ointment was similar to the described for the 10%undecylenic acid solution except that in half of the animals the viruswas introduced by intradermal injection of 0.2 ml of the virus; in theother half of the animals the virus was introduced by spreading thevirus on the skin and lightly scratching the skin with 4 horizontal and4 vertical scratches using a sterile innoculating needle. 20 hours afterinnoculating the animals with the virus, the drug treatment was begun;the ointment was applied three times a day for seven days. After 21 daysof observation, the ointment treated group of animals were no betterthan the placebo group.

EXAMPLE II

Undecylenic acid was evaluated in vitro against herpes I virus todetermine its replication effect.

Green Monkey Kidney tissue cells were grown in micro-Petri dishes insets of twelve duplicates. These sets of tissue culture plates wereinnoculated (except the control set) with the herpes I virus anddifferent concentrations of the drug were added to the wells. Then theseplates were observed for several days and scored by the same person whoequated the severity of the destruction of the cells with an arbitrarynumbering system. These plates were rated according to the percentage ofcells that were destroyed; hence, the higher the number the better theprotection.

Drug concentrations of 1.0, 3.2, and 10.0 micrograms per milliliter wereused on different sets of plates for evaluating the variousconcentrations on the animal tissue cultures. At each of theseconcentrations the percentage of inhibition of virus growth was observedand recorded in Table II.

Comparative parallel evaluations (as a control) were run on a commercialproduct called vidarabine.

                  TABLE II                                                        ______________________________________                                        Effect of Undecylenic Acid and Vidarabine                                     on Herpes Virus Type I                                                        DRUG CON-     INHIBITION OF HERPES                                            CENTRATION    I-REPLICATION                                                   μg/ml      Undecylenic Acid                                                                           Vidarabine                                         ______________________________________                                        0.0   (control)   0            0                                              1.0               74%          0                                              3.2               85%          40%                                            10.0              80%          70%                                            ______________________________________                                         *percent inhibition of virus growth (replication) from untreated control      virus growth. Drugs are dissolved in tissue culture growth media.        

Table II demonstrates that undecylenic acid is effective for inhibitingthe virus growth at 1.0 micrograms per milliliter concentration whereasthe vidarabine drug is not effective until the concentration of 3.2micrograms per milliliter is reached. Furthermore, at the 3.2 microgramsper milliliter concentration the undecylenic acid is twice as effectiveas vidarabine.

What is claimed is:
 1. A method of treating herpes I infection of thelabial area in mammals comprising administering to the mammals in needof said treatment by topical application in the area of said infectionof an effective amount for treating said herpes I infection ofundecylenic acid.
 2. The method of claim 1 wherein the undecylenic acidis applied as a component constituting at least about 10% by weight of acomposition of said undecylenic acid and at least one pharmaceuticallyacceptable carrier.
 3. The process of claim 2 wherein said acid and saidcarrier are in the physical form of a cream.
 4. The process of claim 3wherein said cream comprises sorbitol, polyethylene glycol 300monostearate, stearic acid, anhydrous lanolin, white petrolatum,triethanolamine, methyl paraben, polyoxyethylene laurate, and water. 5.The process of claim 2 wherein said acid and said carrier are in thephysical form of a solution.
 6. The process of claim 5 wherein thesolution comprises propyl alcohol, propylene glycol, triethanolamine,polyoxyethylene 20 sorbitan monooleate, and water.
 7. The process ofclaim 2 wherein said acid and said carrier are in the physical form of alip balm.
 8. The process of claim 7 wherein the lip balm comprisescastor oil, beeswax, butyl stearate, arachidyl propionate and butylatedhydroxytoluene. .[.9. A composition for treating herpes I infectioncomprising an effective amount for treating herpes I infection inmammals of at least about 10% by weight of undecylenic acid and at leastone pharmaceutically acceptable carrier for semi-solid or solid dosageform..]. .[.10. The composition of claim 9 wherein said carriers are inthe form of a cream..]. .[.11. The composition of claim 10 wherein saidcream comprises sorbitol, polyethylene glycol 300 monostearate, stearicacid, anhydrous lanolin, white petrolatum, triethanolamine, andwater..]. .[.12. The composition of claim 9 wherein said carriers are inthe form of a lip balm..]. .[.13. The composition of claim 12 whereinsaid lip balm comprises caster oil, beeswax, butyl stearate, andarachidyl propionate..]. .Iadd.14. A composition for the treatment ofherpes I infections comprising a cream containing at least about 10% byweight of undecylenic acid and sorbitol, polyethylene glycol 300monostearate, stearic acid, anhydrous lanolin, white petrolatum,triethanolamine and water..Iaddend. .Iadd.15. A composition for thetreatment of herpes I infections comprising a lip balm containing atleast 10% by weight of undecylenic acid and castor oil, beeswax, butylstearate and arachidyl propionate..Iaddend.